Recognition, Recognition, Investigation and Investigation and Treatment of Treatment of MyopathiesMyopathies

Hanni BoumaHanni Bouma

August 14, 2013August 14, 2013

OverviewOverview

Statin-induced myopathyStatin-induced myopathy Idiopathic inflammatory Idiopathic inflammatory

myopathiesmyopathies– DermatomyositisDermatomyositis– PolymyositisPolymyositis– Inclusion body myositisInclusion body myositis

Etiological Etiological Classification of Classification of MyopathiesMyopathies HereditaryHereditary Muscular DystrophiesMuscular Dystrophies

– Duchenne’s Duchenne’s MyotoniasMyotonias ChannelopathiesChannelopathies Congenital Congenital

MyopathiesMyopathies Metabolic MyopathiesMetabolic Myopathies

– Pompe’s diseasePompe’s disease Mitochondrial Mitochondrial

myopathiesmyopathies

AcquiredAcquired Inflammatory Inflammatory

myopathiesmyopathies– PM, DM, IBMPM, DM, IBM

EndocrineEndocrine– thyroidthyroid

Associated with Associated with other systemic other systemic illnessillness

Drug-induced and Drug-induced and toxic myopathiestoxic myopathies– EtOH, steroids, EtOH, steroids, statinsstatins

Statin-induced Statin-induced MyopathyMyopathy 1.5-3% of statin users in RCTs and 10-

13% of participants enrolled in prospective clinical studies develop myalgias; rates of myositis lower (~0.1-0.5%) & dose-dependent

Mean duration of statin therapy before Mean duration of statin therapy before onset of Sx.: onset of Sx.: 6 months6 months

Mean duration of myalgias after Mean duration of myalgias after stopping statin therapy: stopping statin therapy: 2 months2 months

QuestionsQuestions

What if a patient develops a What if a patient develops a myopathy after several years of myopathy after several years of taking a statin?taking a statin?

Are some statins more likely to Are some statins more likely to cause muscle damage? Which cause muscle damage? Which ones?ones?

ManagementManagement Significant muscle Sx.: discontinue Significant muscle Sx.: discontinue

statinstatin Asymptomatic but with CK>10x ULN: Asymptomatic but with CK>10x ULN:

discontinue statindiscontinue statin Rhabdo: no statins at any time due to Rhabdo: no statins at any time due to

risk of recurrence risk of recurrence If requires a statin but muscle toxicity If requires a statin but muscle toxicity

other than rhabdo: discontinue statinother than rhabdo: discontinue statin– Once Sx. have resolved and the CK has Once Sx. have resolved and the CK has

returned to baseline, can try returned to baseline, can try pravastatinpravastatin or or fluvastatinfluvastatin with careful monitoring with careful monitoring

QuestionsQuestions

When are EMG or muscle biopsy When are EMG or muscle biopsy necessary in suspected statin necessary in suspected statin myopathy?myopathy?

Is Coenzyme Q10 helpful?Is Coenzyme Q10 helpful?

Statin-associated Statin-associated necrotizing myopathynecrotizing myopathy

Myopathy which persists or Myopathy which persists or progresses after stopping statinprogresses after stopping statin

Linked to autoantibodies against Linked to autoantibodies against HMG-CoA reductaseHMG-CoA reductase

Distinct muscle biopsy findings:Distinct muscle biopsy findings:– macrophagocytic infiltrate engulfing macrophagocytic infiltrate engulfing

necrotic muscle fibers necrotic muscle fibers Responds to immune therapyResponds to immune therapy

Statin-associated Statin-associated necrotizing myopathynecrotizing myopathy

Onto the inflammatory Onto the inflammatory myopathies…myopathies…

DM: ClinicalDM: Clinical

Slow, progressive, symmetric limb-girdle Slow, progressive, symmetric limb-girdle weaknessweakness

Activity-induced muscle painActivity-induced muscle pain Rash usually accompanies or precedes Rash usually accompanies or precedes

weakness (but not always)weakness (but not always) Associated features:Associated features:

– Adults: Myocarditis, ILD, vasculitis, other Adults: Myocarditis, ILD, vasculitis, other CTDs (RA, Scl, CREST)CTDs (RA, Scl, CREST)

– Children: Contractures, subQ calcinosis, Children: Contractures, subQ calcinosis, intestinal ulceration intestinal ulceration

MalignancyMalignancy: : adenocarcinomas, ovarian, adenocarcinomas, ovarian, breast, lung, lymphoma/leukemia breast, lung, lymphoma/leukemia

DM: InvestigationsDM: Investigations

CK normal (20-30%) or increased up to CK normal (20-30%) or increased up to 50x 50x

ANA+ (24-60%) ANA+ (24-60%) Myositis specific antibodies: Myositis specific antibodies:

– Mi-2Mi-2 (15%) (15%) acute onset, nailfold ulcers & good response to acute onset, nailfold ulcers & good response to

therapytherapy– Anti-Jo-1Anti-Jo-1 (~20%) (~20%)

ILD, mechanic’s hands, arthritis, Raynaud’sILD, mechanic’s hands, arthritis, Raynaud’s EMGEMG Muscle biopsyMuscle biopsy MRIMRI

Other Investigations: DMOther Investigations: DM Increased risk of Ca. within first 2-3 yrs of diagnosisIncreased risk of Ca. within first 2-3 yrs of diagnosis

– Treatment of malignancy sometimes improves muscle Treatment of malignancy sometimes improves muscle strengthstrength

– Malignancy workup in all patients: Malignancy workup in all patients: CT CAPCT CAP MammogramMammogram Breast & pelvic examsBreast & pelvic exams ColonoscopyColonoscopy And/OR PET scanAnd/OR PET scan

CXR, High res CT chest (ILD)CXR, High res CT chest (ILD) EKG (myocardial inv’t) or Echo if CHFEKG (myocardial inv’t) or Echo if CHF Swallowing assessment if dysphagiaSwallowing assessment if dysphagia

PolymyositisPolymyositis

““Diagnosis of exclusion” Diagnosis of exclusion” – Often mistaken diagnosis of PM in cases of Often mistaken diagnosis of PM in cases of

DM w/o rash (yet) or IBM w/o inclusions on DM w/o rash (yet) or IBM w/o inclusions on biopsybiopsy

AdultsAdults with prox symmetric weakness: with prox symmetric weakness: limb girdle distribution + neck flexorslimb girdle distribution + neck flexors

Also ass’d with other autoimmune Also ass’d with other autoimmune disordersdisorders

Myocarditis, arthritis, Raynaud’s, ILDMyocarditis, arthritis, Raynaud’s, ILD

IBMIBM Most common myopathy Most common myopathy

> 50 yo> 50 yo Insidious onset; Dx. Insidious onset; Dx.

usually several yrs after usually several yrs after onsetonset

Early dysphagiaEarly dysphagia Different pattern of Different pattern of

weakness: weakness: – Distal UE, Prox LEDistal UE, Prox LE– Early atrophy & Early atrophy &

weakness of WF, FF & weakness of WF, FF & quadsquads

– Hip girdle, TA musclesHip girdle, TA muscles

EMG findingsEMG findings (all IM)(all IM)

Fibs, PSWs, Fibs, PSWs, CRDs at restCRDs at rest

Increased Increased insertional insertional activityactivity

Why fibs?Why fibs?

1) Distal, healthy portion of muscle fibre gets separated from the part attached to the endplate2) Infarction of small intramuscular nerve twigs by surrounding interstitialinflammation

Polyphasic, low Polyphasic, low amplitude, short amplitude, short duration MUPs with duration MUPs with voluntary activationvoluntary activation

Rapid recruitment Rapid recruitment of MUPs w/ full of MUPs w/ full interference interference pattern of low pattern of low amplitude on weak amplitude on weak effort  effort 

EMG findings

Muscle biopsy Muscle biopsy findings…findings…

Diagnosis?Diagnosis?

PMPM

Endomysial mononuclear inflammatory cell infiltrate invading and surrounding non-necrotic muscle fibres

Mediated by CD8+ T-cells which attack Mediated by CD8+ T-cells which attack muscle fibresmuscle fibres

DMDM Humorally-mediated Humorally-mediated

microangiopathymicroangiopathy

1) Perifascicular necrosis/atrophy 2) Perivascular & perimysial inflammation: macrophages, B cells, CD4+ cells

IBMIBM

Similar to PM: CD8+ T cells & macrophagesSimilar to PM: CD8+ T cells & macrophages

Same features as PM + rimmed vacuoles + amyloid depositsModified Gomori trichrome stain

Is it possible to have IBM without Is it possible to have IBM without inclusions on biopsy?inclusions on biopsy?

QuestionQuestion

MRIMRI

•DM: inflammation mainly in anterior muscle compartments w/ preserved muscle mass•PM/IBM: fatty infiltration/muscle atrophy in all muscle groups

Treatment of DM & PMTreatment of DM & PM Overall lack of “EBM” to guide Overall lack of “EBM” to guide

treatment; we don’t know:treatment; we don’t know:– Which second lineWhich second line therapies are most therapies are most

beneficialbeneficial– The doses required to see an effectThe doses required to see an effect– The best time to initiate 2The best time to initiate 2ndnd or 3 or 3rdrd line line

agentsagents– If some agents are more effective in If some agents are more effective in

certain types of myositiscertain types of myositis

Treatment: Step 1Treatment: Step 1Initiate corticosteroidsInitiate corticosteroids

Treatment of choice in DM & PM:Treatment of choice in DM & PM:– Majority of patients will improve with Majority of patients will improve with

pred, but response may be pred, but response may be incompleteincomplete

Start prednisone at ~1 mg/kg/day up Start prednisone at ~1 mg/kg/day up to 100 mg qd to 100 mg qd

In severe weakness, treatment often In severe weakness, treatment often initiated w/ short course of IV initiated w/ short course of IV Solumedrol 1 g x 3 days prior to predSolumedrol 1 g x 3 days prior to pred

Treatment: Step 1Treatment: Step 1Post-initiation of steroidsPost-initiation of steroids

Close clinical F/U q2-4 weeks initiallyClose clinical F/U q2-4 weeks initially Maintain dose until muscle strength Maintain dose until muscle strength

normalizes, improvement plateaus, normalizes, improvement plateaus, or CK normalizes (at least 4-6 wks at or CK normalizes (at least 4-6 wks at high dose)high dose)

Then Then slowslow taper: by taper: by 5 mg q2-3 5 mg q2-3 weeksweeks, below 20 mg by 2.5 q2wks, below 20 mg by 2.5 q2wks

Treatment: Step 1Treatment: Step 1Side effect considerations for steroidsSide effect considerations for steroids

Monitor fasting glucose, K+ levelsMonitor fasting glucose, K+ levels Septra for PCP prophylaxisSeptra for PCP prophylaxis

– If concurrent ILD or pred + other If concurrent ILD or pred + other immunosuppressantimmunosuppressant

Bone density scan at baseline & qyearlyBone density scan at baseline & qyearly Calcium 1 g/day + Vit D 1000 IU/dayCalcium 1 g/day + Vit D 1000 IU/day Bisphosphonate used if postmenopausalBisphosphonate used if postmenopausal Record BP at each visit (accelerated HTN & Record BP at each visit (accelerated HTN &

renal failure is a risk) renal failure is a risk) – Coexistence of scleroderma & other MCTDsCoexistence of scleroderma & other MCTDs

Periodic eye exams for glaucoma & cataractsPeriodic eye exams for glaucoma & cataracts

QuestionQuestion

What should I do if there is no What should I do if there is no response after an adequate trial response after an adequate trial of high dose prednisone?of high dose prednisone?

QuestionQuestion

How can I tell if the patient is How can I tell if the patient is weaker because of refractory weaker because of refractory disease or because of chronic disease or because of chronic steroid use?steroid use?

Treatment: Step 2Treatment: Step 2Add immunosuppressantAdd immunosuppressant

Indications:Indications:– Moderate or severe weaknessModerate or severe weakness– Other organ system inv’t (ILD, Other organ system inv’t (ILD,

myocarditis)myocarditis)– Increased risk of steroid complications Increased risk of steroid complications

(diabetic, OP, postmenopausal women)(diabetic, OP, postmenopausal women)– Failure to significantly improve after 2-4 Failure to significantly improve after 2-4

months of steroidsmonths of steroids– Any pt expected to need steroids for 10-12 Any pt expected to need steroids for 10-12

mos or moremos or more

Treatment: Step 2Treatment: Step 2ImmunosuppressionImmunosuppression

Options:Options:– AzathioprineAzathioprine – MethotrexateMethotrexate– IVIG IVIG – CellceptCellcept– CyclophosphamidCyclophosphamid

ee

Generally used Generally used as 3as 3rdrd line, if line, if refractory to refractory to other Rx.:other Rx.:– Rituximab Rituximab – PLEX PLEX – CiclosporineCiclosporine– TacrolimusTacrolimus

AzathioprineAzathioprine

Effective in DM/PM (retrospective Effective in DM/PM (retrospective studies), but takes 6-18 mos to studies), but takes 6-18 mos to workwork

Prior to starting, can screen for Prior to starting, can screen for TPMT deficiency (BM toxicity in TPMT deficiency (BM toxicity in homozygotes) or just monitor CBChomozygotes) or just monitor CBC

Begin at 50 mg/d, increase by 50 Begin at 50 mg/d, increase by 50 mg q2wks up to 2-3 mg/kg/dmg q2wks up to 2-3 mg/kg/d

AzathioprineAzathioprineMonitoring & SEsMonitoring & SEs

Major SEs:Major SEs: 12% develop systemic 12% develop systemic rxn (fever, abdo pain, N/V) within rxn (fever, abdo pain, N/V) within first few wks requiring first few wks requiring discontinuation of drug; BM & liver discontinuation of drug; BM & liver toxicity, pancreatitis, teratogenicity, toxicity, pancreatitis, teratogenicity, oncogenicity, infectiononcogenicity, infection

LeukopeniaLeukopenia Monitor CBC, LFTs closelyMonitor CBC, LFTs closely

MethotrexateMethotrexate

Most DM & PM respond to MTX Most DM & PM respond to MTX (retrospective studies only)(retrospective studies only)

Begin at 7.5 mg/wk po, increase Begin at 7.5 mg/wk po, increase gradually by 2.5 mg each week gradually by 2.5 mg each week up to 25 mg/wkup to 25 mg/wk

If no improvement after 1 month If no improvement after 1 month on 25 mg, switch to weekly subQ on 25 mg, switch to weekly subQ & increase dose by 5 mg qwk up & increase dose by 5 mg qwk up to 60 mg/wkto 60 mg/wk

MethotrexateMethotrexateMonitoring & SEsMonitoring & SEs

Major SEs:Major SEs: alopecia, stomatitis, alopecia, stomatitis, pulmonary fibrosis, pulmonary fibrosis, teratogenicity, teratogenicity, oncogenicity, infection; renal, liver oncogenicity, infection; renal, liver & BM toxicity& BM toxicity

Avoid MTX in pts with ILD or anti-Avoid MTX in pts with ILD or anti-Jo-1+Jo-1+

Avoid MTX in heavy drinkersAvoid MTX in heavy drinkers Treat all pts with folate 5 mg qwkTreat all pts with folate 5 mg qwk

IVIGIVIG

One prospective, double-blind, One prospective, double-blind, placebo-controlled study in 15 pts placebo-controlled study in 15 pts w/ DM showed significant w/ DM showed significant improvementimprovement

Little RCTLittle RCT evidence of benefit as evidence of benefit as monotherapy but plenty of monotherapy but plenty of anecdotal evidence that IVIG is anecdotal evidence that IVIG is effective, even aloneeffective, even alone

CyclophosphamideCyclophosphamide

Used often if ILDUsed often if ILD SEs: infections, secondary SEs: infections, secondary

malignancies, hemorrhagic malignancies, hemorrhagic cystitis, sterilization, BM toxicity, cystitis, sterilization, BM toxicity, GI upset, alopeciaGI upset, alopecia– Usually given pulsed; higher risk of Usually given pulsed; higher risk of

cystitis pocystitis po

Treatment: Step 3Treatment: Step 3If refractory to other modalities…If refractory to other modalities…

RituximabRituximab -> monoclonal Ab -> monoclonal Ab against CD20, depletes B cellsagainst CD20, depletes B cells– Warnings re: PML risk…Warnings re: PML risk…

SISide Effects & Side Effects & MonitoringMonitoring

Non-medical therapiesNon-medical therapies

PT & OTPT & OT Dietician consult if on steroidsDietician consult if on steroids Aerobic exercise programsAerobic exercise programs

– Prevents contracturesPrevents contractures– May help w/ steroid SEs (weight May help w/ steroid SEs (weight

gain, OP, type 2 fibre atrophy)gain, OP, type 2 fibre atrophy) Speech therapySpeech therapy

– Esp if concomitant dysphagiaEsp if concomitant dysphagia

QuestionQuestion

What is the value of monitoring What is the value of monitoring serum CK levels in the treatment serum CK levels in the treatment of DM & PM?of DM & PM?

QuestionQuestion

How does the treatment of IBM How does the treatment of IBM differ from that of PM & DM?differ from that of PM & DM?

IBMIBM

Glucocorticoids have limited roleGlucocorticoids have limited role– In largest published series, muscle In largest published series, muscle

strength continued to deteriorate in strength continued to deteriorate in all of 25 pred-treated patients all of 25 pred-treated patients followed for at least 2 yrsfollowed for at least 2 yrs

– CK levels often normalize, but this CK levels often normalize, but this doesn’t correlate with clinical benefitdoesn’t correlate with clinical benefit

IBM: suggested IBM: suggested approachapproach If ++inflammation seen on Bx., If ++inflammation seen on Bx.,

consider trial of steroids +/- consider trial of steroids +/- Imuran (3 mos) early in diseaseImuran (3 mos) early in disease

Discontinue all therapy if Discontinue all therapy if continued decline in strengthcontinued decline in strength

For most patients, For most patients, no treatmentno treatment

Overview of the IMOverview of the IM

ReferencesReferences

Dr. Erin O’FerrallDr. Erin O’Ferrall Amato & Barohn. Evaluation and treatment Amato & Barohn. Evaluation and treatment

of inflammatory myopathies. of inflammatory myopathies. Journal of Journal of Neurology, Neurosurgery & Psychiatry Neurology, Neurosurgery & Psychiatry 2009; 2009; 80: 1060-1068.80: 1060-1068.

Sathasivam & Lecky. Statin induced Sathasivam & Lecky. Statin induced myopathy. myopathy. BMJ BMJ 2008; 337: a2286.

Preston & Shapiro. Electromyography and neuromuscular disorders: Clinical-electrophysiologic correlates. 2nd ed. 2005.

Up to Date: Statin myopathy & Up to Date: Statin myopathy &